The innate immune system is responsible for the elimination of most pathogens encountered by a healthy individual. Several defects in innate immunity have been associated with HIV-1 infection resulting in increased susceptibility to opportunistic and secondary infections. The underlying mechanisms for innate immune dysfunction during HIV-1 infection are largely unexplored. A family of receptors that recognize pathogen-associated molecular patterns (PAMP) have been identified in humans and are called toll-like receptors (TLR). It is now clear that TLR provide some specificity to the innate immune response as a result of the PAMP recognized, the cellular distribution of different TLR, and the unique down-stream effects of TLR ligation and signal transduction. TLR are at the initial interface between a potential pathogen and the immune system, and in this role, TLR initiate the inflammatory response and induce the adaptive immune response. Because of the pivotal role of TLR in immune responses, it is reasonable to consider whether HIV-1 affects TLR function as has been observed with several other viruses. Here we propose to address three questions: Firstly, does HIV induce signal transduction through TLR that could lead to chronic immune stimulation or target cell recruitment? Secondly, does HIV-1 affect TLR expression? Thirdly, does HIV-1 impair TLR function. Through these studies we will learn if HIV/TLR interaction contribute to the immunodeficiency caused by HIV-1.